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Background The management of osteochondral lesions of the talus (OLT) is challenging, with 2 main options being conservative and surgical management. Orthobiologic therapies come to bridge the gap between these 2 options; however, inconsistencies in indication, composition, and heterogeneous evidence limit clinical decision-making. To address these challenges, 3 International Congress Meetings on Cartilage Repair of the Ankle were convened in Pittsburgh, USA (2017), Dublin, Ireland (2019), and New York, USA (2025) to establish agreement on the role of conservative management and injectable orthobiologic strategies in the treatment of OLT. Methods Seventy-five multidisciplinary experts from over 25 countries and 1 territory participated in a structured Delphi-based consensus process. Blinded surveys, structured questionnaires, and in-person discussions were used to develop and refine statements, supported by literature review and graded evidence (A1–E). Consensus strength was defined as consensus (51%-74%), strong consensus (75%-99%), or unanimous (100%) Results In total, 29 consensus statements were achieved across the 3 meetings. Strong agreement was reached regarding indications and expected outcomes of conservative management, including the role of immobilization and appropriate timing for surgical intervention. Orthobiologic injections, including platelet-rich plasma, concentrated bone marrow aspirate, and hyaluronic acid, were considered appropriate in select patients with persistent symptoms, although no superiority was demonstrated among formulations, preparation methods, or injection strategies. When used as adjuncts to surgical procedures, orthobiologics may improve radiological outcomes, with limited evidence for improvement in clinical outcomes. Technical considerations, including preferred harvest sites and a lack of standardized preparation protocols, were identified, along with key principles for patient counseling Conclusion These international consensus statements establish a standardized framework for the conservative management and use of injectable orthobiologic therapies in OLT. By clarifying indications, technical considerations, and current limitations, this work aims to improve consistency in clinical practice, guide treatment decision-making, and inform future research.

BACKGROUND AND OBJECTIVES: This study proposes and assesses the validity of postoperative dysphagia severity categories based on patients' Eating Assessment Tool-10 (EAT-10) scores and quality-of-life patient-reported outcome measures (PROMs) collected before and after cervical spine surgery. METHODS: A prospectively collected multi-institutional quality registry including 2003 patients was retrospectively reviewed. Patients were categorized based on EAT-10 score severities, with thresholds determined by existing literature and significant differences in PROMs: none (0-2), mild (3-4), moderate (5-15), and severe (16-40). Correlations between EAT-10 severity and established PROMs were assessed at baseline, 3-, and 12-month follow-ups. The Dunn test using Bonferroni adjustment was used to identify differences in PROMs between EAT-10 severities. Multivariate linear regression assessed how EAT-10 severity affects PROMs at baseline, 3-, and 12-month follow-ups. RESULTS: Among 1659 patients with 3-month EAT-10 data, there were 1183 no, 149 mild, 245 moderate, and 82 severe dysphagia patients. Neck Disability Index and EuroQol 5-Dimension scores were significantly different between none vs mild ( P < .001; P = .001), mild vs moderate ( P < .001; P < .001), and moderate vs severe ( P = .035; P = .024) at 3 months. Among 1405 patients with 12-month EAT-10 data, there were 1044 no, 100 mild, 194 moderate, and 67 severe dysphagia patients. Neck Disability Index scores were significantly different between none vs mild ( P < .001) and moderate vs severe ( P = .004) but not for mild vs moderate ( P > .9) at 12 months. EuroQol 5-Dimension scores were significantly different between none vs mild ( P = .004) and mild vs moderate ( P = .005) but not for moderate vs severe ( P = .08). In multivariate regression, EAT-10 severity categories independently predicted worse PROMs at all time points. CONCLUSION: We propose none (0-2), mild (3-4), moderate (5-15), and severe (16-40) dysphagia categories based on EAT-10 scores. Evidence from univariate and multivariate analyses strengthens the validity of our proposed EAT-10 severity categories, providing statistical justification for their incorporation into clinical practice.

Abstract Aims Randomized trials comparing percutaneous left atrial appendage occlusion (LAAO) with oral anticoagulation (OAC) for stroke prevention in patients with atrial fibrillation have yielded conflicting results across device generations and anticoagulant eras. This Bayesian meta-analysis of randomized trials aimed to compare LAAO vs. OAC for stroke or systemic embolism (SSE) and non-procedural clinically relevant bleeding (CRB). Methods and results We conducted a systematic search across five databases (PubMed, Embase, Scopus, Web of Science, and Cochrane CENTRAL) to identify randomized trials of LAAO vs. OAC. Primary outcomes of stroke or systemic embolism, non-procedural CRB and clinical benefit composite were estimated using a Bayesian hierarchical random effects model and findings confirmed across robust sensitivity and subgroup analyses. Posterior probabilities for superiority, non-inferiority and equivalence were estimated using clinically meaningful margins. Six randomized trials including 7004 participants in the intention-to-treat groups, were analysed. LAAO was not associated with lower SSE vs. OAC (pooled RR, 1.11; 95% CrI, 0.80–1.49), with a 74.6% posterior probability of favouring OAC. The posterior probability of crossing non-inferiority was P(HR &lt; 1.4) of 89%. In contrast, LAAO reduced non-procedural CRB (pooled RR, 0.59; 95% CrI, 0.45–0.78). The net clinical benefit composite, pooling contemporary trials, demonstrated a pooled RR of 0.90 (95% CrI 0.51–1.50), with P(RR &lt; 1) of 76%, with substantial heterogeneity for this outcome. Conclusion This Bayesian meta-analysis found no clear evidence supporting clinically meaningful non-inferiority of LAAO over OAC for stroke prevention. Despite reduced non-procedural bleeding, LAAO did not demonstrate a similar reduction in major bleeding.

Solitary plasmacytomas (SPs) are rare localized tumors of clonal plasma cells, either in the bone (solitary bone plasmacytoma) or in soft tissue/extraosseous (extramedullary) with either no or with minimal bone marrow (BM) infiltration (<10% clonal plasma cells by immunohistochemistry) and no evidence of systemic involvement or myeloma defining events. Approximately 50% of SPs will progress to symptomatic myeloma within 5 years after initial definitive local radiotherapy. Increased availability of improved diagnostic and monitoring tools has increased the sensitivity of detection of additional lesions and marrow involvement and has implications for the follow-up strategy after treatment. Thus, the definitions and requirements for the diagnosis and follow-up of SPs are evolving. The diagnosis of SP requires the careful exclusion of multiple myeloma (MM) that would require systemic therapy, by using all the available methods to detect systemic disease (advanced imaging, sensitive BM assessment methods, blood and urine tests). Local radiotherapy remains the mainstay of therapy, and despite the availability of innovative drugs for MM, the clinical benefit of systemic therapy currently remains poorly defined. The International Myeloma Working Group provides here updated recommendations for the diagnosis, evaluation, treatment, and response assessment of patients with SPs, incorporating recent data and advances in diagnostic tools.

Abstract Background Appendectomy has been proposed to influence ulcerative colitis (UC) outcomes, but its effect based on timing before or after diagnosis and long-term UC outcomes remains unclear. Materials and Methods Using TriNetX U.S. Collaborative Network, we identified adults with UC (2010-2024) who underwent appendectomy before or after diagnosis. Two 1:1 propensity score-matched comparisons were performed: appendectomy-before-UC and appendectomy-after-UC versus controls. The primary outcome was a 5-year composite of oral/intravenous (IV) corticosteroid use or colectomy. Secondary outcomes included individual composite outcomes and advanced therapy initiation in biologic-naive patients. Subgroup analyses stratified by age and biologic exposure were also performed. Results After matching, appendectomy after UC diagnosis showed no association with the composite outcome (aHR 0.98, 95% CI, 0.83-1.16), oral steroids (aHR 0.90, 95% CI, 0.75-1.09), IV steroids (aHR 1.11, 95% CI, 0.87-1.43), colectomy (aHR 1.24, 95% CI, 0.77-1.99), or advanced therapy initiation (aHR 0.97, 95% CI, 0.63-1.48). Appendectomy before UC diagnosis also showed no difference in the composite outcome (aHR 0.91, 95% CI, 0.76-1.09), oral steroids (aHR 0.88, 95% CI, 0.72-1.08), colectomy (aHR 0.99, 95% CI, 0.60-1.63), or advanced therapy initiation (aHR 0.77, 95% CI, 0.53-1.13). However, IV steroid use was reduced (aHR 0.68, 95% CI, 0.51-0.90, P = .006). In subgroup analyses, advanced therapy initiation was lower in patients aged 18-40 years following appendectomy after UC diagnosis (aHR 0.56, 95% CI, 0.33-0.96, P = .03). Conclusion Appendectomy was not associated with improved long-term UC outcomes of oral/IV steroid use, colectomy or initiation of advanced therapy regardless of timing.

Most genetic variants associated with complex traits are hypothesized to regulate gene expression. To understand the genetics underlying gene expression variability, we characterized 14,324 RNA-sequencing samples from the Trans-Omics for Precision Medicine program and performed expression and splicing quantitative trait locus (e/sQTL) analyses in six tissues and cell types, including whole blood ( n = 6454) and lung ( n = 1291). We detected tens of thousands of secondary cis-e/sQTLs, showing that secondary cis-e/sQTL discovery remains unsaturated. We fine-mapped UK Biobank–derived genome-wide association study (GWAS) signals from 164 traits and identified e/sQTL colocalizations for 10,611 GWAS signals, including 7096 that colocalize with secondary e/sQTLs. Our results suggest that even larger e/sQTL analyses will uncover additional secondary e/sQTLs, further benefiting GWAS interpretation.

Importance Ischemic heart disease (IHD), the leading cause of death in the US, is predominantly due to modifiable risk factors. Estimates of IHD mortality attributable to risk factors provide evidence for health policy decision-making. Objective To estimate the burden of IHD death attributable to risk factors in the US from 1990-2023. Design, Setting, and Participants The Global Burden of Disease Study 2023 (GBD 2023) used vital records and a broad set of epidemiologic data to estimate IHD death rates, risk factor exposure, and relative risk curves for risk-outcome pairs for 1990-2023 for the general population. Data analysis was performed from October 2024 to December 2025. Exposure Twelve metabolic, behavioral, and environmental risk factors. Main Outcomes and Measures The primary outcomes were IHD death rates per 100 000 persons, counts, and attributable risks from 1990-2023 by age, sex, and US state. Estimates include 95% uncertainty intervals (UI). IHD death rates were estimated using ensemble modeling methods. Risk exposures were estimated using bayesian meta-regression methods. Relative risks were estimated following the Burden of Proof framework. Results In 2023, there were 473 000 IHD deaths (95% UI, 414 000-510 000) in the US, a decrease of 58.7% (95% UI, 56.8%-61.0%) in age-standardized rate since 1990. Between 2010 and 2023, there was a 19.0% decrease (95% UI, 15.0%-22.9%) for males and a 24.5% decrease (95% UI, 20.3%-29.7%) for females in IHD death rates. High systolic blood pressure (SBP), dietary risks, and high low-density lipoprotein cholesterol (LDL-C) were the leading risk factors for IHD deaths in 2023, accounting for 47.2% (95% UI, 36.4%-57.0%), 38.6% (95% UI, 17.2%-56.8%), and 28.5% (95% UI, 19.3%-39.6%) of IHD deaths, respectively. Increased exposure to several risk factors substantially increased their attributable burden for IHD deaths in 2023, with high fasting plasma glucose (FPG) increasing 38.8% (95% UI, 11.5%-81.1%) and high body mass index (BMI) increasing 54.5% (95% UI, 41.8%-66.3%) since 1990. Smoking and particulate matter pollution had the greatest decrease in attributable IHD mortality since 1990, at 33.3% (95% UI, 23.6%-41.7%) and 74.9% (95% UI, 46.7%-88.8%), respectively. Conclusion and Relevance Per the results of this systematic analysis of GBD 2023, a total of 88.7% (95% UI, 83.4%-92.5%) of IHD deaths were attributable to modifiable risk factors in the US in 2023, with high SBP, dietary risks, and high LDL-C being the greatest contributors. High BMI and high FPG showed the largest attribution increases, while exposure to other risks did not increase significantly for the population.

ABSTRACT Background Diagnostic interpretation of kidney allograft biopsies using the Banff classification remains variable, but the determinants of this variability are not fully defined. We performed a global, fully digital multi-reader study to identify the principal drivers of disagreement in Banff-based assessment. Methods Thirty-six kidney transplant biopsies were independently scored by 67 renal pathologists on a standardized digital platform. Readers assessed Banff lesions on hematoxylin and eosin, periodic acid–Schiff, and Jones’ silver stains; final diagnostic categories were assigned using prespecified Banff-based decision rules. Interobserver agreement was quantified with Gwet’s agreement coefficient (AC) statistics. Determinants of diagnostic agreement were evaluated using pairwise mixed-effects logistic regression, and reader similarity was examined by principal component analysis (PCA) with post hoc molecular annotation. Results Agreement for final diagnostic categories was moderate (Gwet’s AC1, 0.55; 95% CI, 0.47–0.63). Lesion-level agreement varied substantially, with lowest agreement for selected threshold-dependent inflammatory or semi-quantitative lesions, including interstitial inflammation in areas of IFTA, peritubular capillaritis and arteriolar hyalinosis. Diagnostic concordance differed markedly across biopsies, indicating strong case-level heterogeneity. In pairwise models, differences in active inflammatory and vascular lesion scoring were the strongest correlates of diagnostic disagreement; reader experience and geography contributed minimally. Principal component analysis showed reader variation was organized along two dominant axes: a rejection-calling threshold axis linked mainly to tubulointerstitial inflammatory injury, and a T cell-mediated (TCMR/TI) and antibody-mediated/microvascular (AMR/MVI) inflammation-oriented phenotypic classification axis. Conclusion Interobserver variation in Banff-based kidney transplant biopsy assessment is structured rather than random and driven mainly by how readers threshold and integrate key inflammatory lesion compartments rather than experience or geographic location.

Importance Amyloid positron emission tomography (PET) is increasingly used in research and clinical settings to determine the etiology of cognitive decline and eligibility for amyloid-targeting therapies. To assist with amyloid PET evaluation and to guide clinical decision-making, images can be quantified in a standardized unit called Centiloid, the interpretation of which can vary according to the method and threshold used. Objective To collect Centiloid values from available studies and determine robust positivity cutoffs using data-driven methods and correspondence with visual reads. Data Sources PubMed search (October 2024) identified studies with Centiloid values. Corresponding authors were invited to share individual participant data. Additional data were obtained through access-controlled repositories and conference outreach (July 2024-July 2025). Study Selection Studies were included if they provided Centiloids, radiotracer, age, and sex. Data Extraction and Synthesis Each study was analyzed using a unified statistical pipeline; study estimates were pooled using random-effects meta-analysis. Main Outcomes and Measures Gaussian mixture models (GMMs) were fitted to Centiloid values for each study. In studies with a bimodal distribution (per integrated completed likelihood), single cutoffs for positivity were set as mean plus 2 SDs of the lower gaussian component. Using GMMs, a double-cutoff approach defined a lower certainty range using a 90% posterior probability cutoff for assignment to the low (amyloid-negative) vs high (amyloid-positive) component. An alternative Centiloid cutoff was derived from maximizing the correspondence (Cohen κ) with the binary visual reads when available. Results This meta-analysis included cross-sectional amyloid PET scans acquired with 5 radiotracers from 49 227 participants across 53 studies from 15 countries (mean age, 71 years; 54% female, 62% cognitively impaired). The data-driven GMM approach identified a bimodal distribution in 51 studies (n = 48 786), resulting in a single cutoff for positivity of 18 Centiloids (95% CI,16-19; I 2 = 97%). The double-cutoff approach revealed high confidence for interpreting scans as negative when Centiloid values were lower than 11 (95% CI, 9-13; I 2 = 95%) and interpreting scans as positive if Centiloid values were higher than 26 (95% CI, 24-28; I 2 = 95%). In analyses of correspondence with binary (positive or negative) visual reads of amyloid PET scans (n = 35 045; 36 studies), Centiloids were highly predictive of visual positivity (Cohen κ, 0.86; 95% CI, 0.83-0.89; I 2 = 96%) with a cutoff of 27 Centiloids (95% CI, 24-30; I 2 = 80%). Conclusions and Relevance In this individual participant data meta-analysis, positivity cutoffs converged around 18 Centiloids (data-driven) and 27 Centiloids (visual reads). Findings from a double-cutoff analysis suggest that scans in the 11 to 26 Centiloid range should be interpreted with caution depending on the context of use.